Methods to synthesize small molecules are in transition in many pharmaceutical and biotechnology companies. The value of solution phase parallel synthesis is now widely recognized. Small targeted (focused) libraries made up of 50-200 compounds are increasingly popular for lead optimization projects, and compound libraries with high molecular diversity are given more consideration for discovery libraries. Quantities for testing or deposition in compound collections are increasing to the 10-50 mg range, and requirements for purity have stiffened (90% or better is now common). These needs tax current solution phase methodology to its limits because of time-consuming and often difficult separations. Fluorous Technologies, Inc. (FTI) is developing a broad-based technology platform that comprehensively addresses the demanding synthetic chemistry needs in a modem drug discovery environment. Based on two successful Phase I projects, the current Phase II grant strives to develop a rapid fluorous synthesis toolkit for solution-phase parallel library synthesis. The specific aims of this research effort are: 1) to develop new fluorous scavengers, tags, and protecting groups while simultaneously expanding the scope to include new fluorous reagents, catalysts, and reactants; 2) to expand the scope of microwave technology in fluorous synthesis; 3) to further strengthen the fluorous separation technology by developing new fluorous chromatographic and parallel SPE methods; 4) to develop a "rapid fluorous synthesis" toolkit by using a combination of fluorous chemicals, microwave technology, and fluorous silica gel-based separations. The toolkit includes three different protocols: a one-hour single reaction, one-day one-step parallel synthesis, and one-week multi-step library synthesis; 5) to validate rapid fluorous synthesis in solution phase library production by making 5 prototype libraries with pharmaceutically interesting scaffolds, containing 100-200 analogs, 10-50 mg each, and in greater than 90% purity. [unreadable] [unreadable]